A novel approach to discover selective small molecule inhibitors of FABP4 and FABP5 for the treatment of metabolic diseases The Western diet and lifestyle has brought an epidemic of health problems collectively referred to as metabolic syndrome. Obesity plays a central role, contributing to type 2 diabetes, fatty liver disease, atherosclerosis, and degenerative disorders including dementia, airway diseases, and even some cancers. Diet and exercise are the best means to tackle metabolic diseases but often fail to halt disease progression, and pharmacological intervention is often necessary. Among the many potential drug targets for tackling metabolic disorders, two members of the family of fatty acid-binding proteins (FABPs) are particularly compelling. The FABPs consist of nine distinct but closely related proteins;as their name suggests, they play major roles in transporting fatty acids throughout cells and in maintaining metabolic homeostasis. Experiments in rodents suggest that reducing the activity of either FABP4 or FABP5 has moderate effects on a variety of metabolic indicators, but that reducing the activity of both FABP4 and FABP5 provides significant benefits protecting against obesity, insulin resistance, atherosclerosis, and even extends lifespan. However, effective and safe drugs must be highly selective: reducing the activity of FABP2 causes weight gain and elevated insulin levels, while reducing the activity of FABP3 causes heart problems. This Phase I SBIR has three specific aims. In the first aim, Carmot will apply a novel small molecule lead discovery technology called Chemotype Evolution to FABP4 with the goal of discovering at least 20 potent inhibitors. Chemotype Evolution is a fragment-based approach designed to find selective inhibitors against difficult protein targets, and so fulfilling the first goal will not only identify useful molecules but also demonstrate that the technology can deliver a wide variety of starting points for a therapeutically important target. In the second aim, Carmot will explore selectivity against FABP2, FABP3, and FABP5. The goal is to discover at least 5 compounds with high potency against both FABP4 and FAPB5 and good selectivity against FABP2 and FABP3. This will demonstrate that the technology can deliver selective inhibitors against closely related members of a single protein family. The third aim is to identify at least two compounds with the desired selectivity profile that also show good cell-based potency. These molecules will certainly be useful tools for dissecting the FABP pathways. More importantly, these molecules could be potential therapeutics for treating a variety of metabolic diseases, including obesity and diabetes. The goal of a Phase II SBIR would be to further develop the resulting molecules in preclinical animal models prior to human development. PUBLIC HEALTH RELEVANCE: A novel approach to discover selective small molecule inhibitors of FABP4 and FABP5 for the treatment of metabolic diseases This proposal is to use a powerful new drug discovery technology to identify highly selective inhibitors of two proteins implicated in a variety of metabolic diseases. These inhibitors will become the starting points for new therapeutics to treat unmet medical needs such as obesity and diabetes.